Cannabis is the most widely used illegal drug and it has been linked with numerous serious adverse effects. Cannabis has also been proposed as useful therapy for several neurological conditions including chronic pain, AIDS-related muscle wasting, and movement disorders. Detailed knowledge about the mechanisms by which this drug acts is crucial to understanding its many effects, and may greatly assist in the design of drugs to facilitate treatment of cannabis dependence and the above diseases. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on the distribution and function in the brain of the extracellular Ca-sensing receptor (CaSR) it has been suggested that it a potential target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), localized in the majority of nerve terminals in the brain, and activation of CaSR modulates synaptic transmission. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanisms of cannabinoid action. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and whether brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR and substantially change the thinking in this field. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and several neurological diseases. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence, but has also been proposed as therapy for several illnesses including chronic pain, cancer and AIDS-related wasting. New improved treatments are needed but this requires improved understanding of how cannabis works. We have discovered a new pathway in the brain that is activated by cannabis-like drugs. By studying this new pathway we will discover more about how cannabis works and so improve the chances of designing new treatments to help in the fight against drug dependence and many serious diseases.